Labetolol

Uses

Labetolol Hydrochloride is used for the control of all grades of hypertension including-

• Pregnancy-induced hypertension
• The treatment of angina in patients with hypertension
• Where a hypertensive technique is used for anesthesia
• The management of catecholamine excess and patients with pheochromocytoma.

Labetolol is also used to associated treatment for these conditions: Chronic Stable Angina Pectoris, High Blood Pressure (Hypertension), Hypertensive Emergency, Hypertensive crisis, Pheochromocytomas, Subarachnoid Hemorrhage

How Labetolol works

Labetolol non-selectively antagonizes beta-adrenergic receptors, and selectively antagonizes alpha-1-adrenergic receptors. Following oral administration, labetalol has 3 times the beta-blocking ability than alpha-blocking ability. This increases to 6.9 times following intravenous administration. Antagonism of alpha-1-adrenergic receptors leads to vasodilation and decreased vascular resistance. This leads to a decrease in blood pressure that is most pronounced while standing. Antagonism of beta-1-adrenergic receptors leads to a slight decrease in heart rate. Antagonism of beta-2-adrenergic receptors leads to some of the side effects of labetalol such as bronchospasms, however this may be slightly attenuated by alpha-1-adrenergic antagonism. Labetolol leads to sustained vasodilation over the long term without a significant decrease in cardiac output or stroke volume, and a minimal decrease in heart rate.

Dosage

Labetolol dosage

Oral-

Adult: The recommended initial dosage is 100 mg twice daily whether used alone or added to a diuretic regimen. After 2 or 3 days, using standingblood pressureas an indicator, dosage may be titrated in increments of 100 mg b.i.d. every 2 or 3 days. The usual maintenance dosage of labetalol HCl is between 200 and 400 mg twice daily.

Since the full antihypertensive effect of labetalol HCl is usually seen within the first 1 to 3 hours of the initial dose or dose increment, the assurance of a lack of an exaggeratedhypotensiveresponse can be clinically established in the office setting. The antihypertensive effects of continued dosing can be measured at subsequent visits, approximately 12 hours after a dose, to determine whether further titration is necessary.

Patients with severe hypertension may require from 1,200 to 2,400 mg per day, with or without thiazide diuretics. Should side effects (principallynauseaor dizziness) occur with these doses administered twice daily, the same total daily dose administered three times daily may improve tolerability and facilitate further titration. Titration increments should not exceed 200 mg twice daily.

When a diuretic is added, an additive antihypertensive effect can be expected. In some cases this may necessitate a labetalol HCl dosage adjustment. As with most antihypertensive drugs, optimal dosages of Labetolol Tablets are usually lower in patients also receiving a diuretic.

When transferring patients from other antihypertensive drugs, Labetolol Tablets should be introduced as recommended and the dosage of the existing therapy progressively decreased.

Elderly: As in the general patient population, labetalol therapy may be initiated at 100 mg twice daily and titrated upwards in increments of 100 mg b.i.d. as required for control of blood pressure. Since some elderly patients eliminate labetalol more slowly, however, adequate control of blood pressure may be achieved at a lower maintenance dosage compared to the general population. The majority of elderly patients will require between 100 and 200 mg b.i.d.

Injection-

Adults:

• Bolus Injection: If it is essential to reduce the blood pressure quickly a dose of 50 mg should be given by intravenous injection (over a period of at least one minute) and, if necessary, repeated at five minute intervals until a satisfactory response occurs. The total dose should not exceed 200 mg.
• Intravenous Infusion: For intravenous infusion the injection should be diluted with a suitable intravenous infusion fluid to a concentration of Labetolol Hydrochloride 1 mg/1 ml. Compatible fluids include 5% Dextrose; 0.9% Sodium Chloride; Dextrose and Sodium Chloride.
• Hypertension in pregnancy: Infusion should be started at 20 mg/hour, then doubled every 30 minutes until a satisfactory response is obtained or a dosage of 160 mg/hour is reached.
• Hypertensive episodes following acute myocardial infarction: Infusion should be started at 15 mg/hour and gradually increased to a maximum of 120 mg/hour depending on the control of blood pressure.
• Hypertension due to other causes: Infuse at a rate of about 2 mg/min until a satisfactory response is obtained, then stop infusion. The effective dose is usually 50-200 mg but larger doses may be needed, especially in patients with phaeochromocytoma. The rate of infusion may be adjusted according to the response at the discretion of the physician. Labetolol injection has been administered to patients with uncontrolled hypertension already receiving other hypotensive agents, including b-blocking drugs, without adverse effects.
• Hypotensive anaesthesia: Induction should be with standard agents (e.g. sodium thiopentone) and anaesthesia maintained with nitrous oxide and oxygen with or without halothane. The recommended starting dose of Labetolol injection is 10-20 mg intravenously depending on the age and condition of the patient. Patients for whom halothane is contraindicated usually require a higher initial dose of Labetolol (25-30 mg). If satisfactory hypotension is not achieved after five minutes, increments of 5-10 mg should be given until the desired level of blood pressure is attained. Halothane and Labetolol act synergistically therefore the halothane concentration should not exceed 1-1.5% as profound falls in blood pressure may be precipitated.

Children: Safety and efficacy in children have not been established.

Side Effects

Adverse effects reported are postural hypotension (avoid upright position during and for 3 hours after intravenous administration), tiredness, weakness, headache, rashes, scalp tingling, difficulty in micturition, epigastric pain, nausea, vomiting, liver damage.

Toxicity

The oral LD₅₀ in mice is 600mg/kg and in rats is >2g/kg. The intravenous LD₅₀ in mice and rats is 50-60mg/kg.

Patients experiencing an overdose may present with excessive hypotension and bradycardia. Patients should be placed on their back with their legs raised to maintain perfusion of the brain. Oral overdoses may be treated with gastric lavage or emesis, bradycardia may be treated with atropine or epinephrine, cardiac failure may be treated with digitalis and a diuretic, hypotension may be treated with vasopressors, bronchospasms may be treated with epinephrine or a beta₂ agonist, and seizures may be treated with diazepam.

Precaution

Patients with phaeochromocytoma, inadequate cardiac function and well-compensated heart failure, DM, nonallergic bronchospasm. Patients undergoing major surgery involving general anaesth. May mask symptoms of hypoglycaemia. Avoid abrupt withdrawal as it may exacerbate angina. Hepatic impairment. Elderly, pregnancy and lactation.

Interaction

Synergistic hypotensive effect with halothane. Increased absolute bioavailability with cimetidine. Decreased absolute bioavailability with glutethimide. Additive hypotensive effect with nitroglycerin. Increased incidence of tremor with TCAs. Increased risk of bradycardia and heart block with Ca channel blocker (e.g. verapamil, diltiazem).

Food Interaction

• Take with or without food. The absorption is unaffected by food.

Labetolol Alcohol interaction

[Moderate]

Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation.

Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

Caution and close monitoring for development of hypotension is advised during coadministration of these agents.

Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs.

Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

Labetolol Cholesterol interaction

[Moderate] Beta-adrenergic receptor blocking agents (aka beta-blockers) may alter serum lipid profiles.

Increases in serum VLDL and LDL cholesterol and triglycerides, as well as decreases in HDL cholesterol, have been reported with some beta-blockers.

Patients with preexisting hyperlipidemia may require closer monitoring during beta-blocker therapy, and adjustments made accordingly in their lipid-lowering regimen.

Labetolol multivitamins interaction

[Moderate] ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers.

The exact mechanism of interaction is unknown.

In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively.

The elimination half-life increased by 44%.

Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone.

However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments.

The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours.

Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

Labetolol Drug Interaction

Moderate: furosemide, furosemide, amlodipine, amlodipineMinor: aspirin, aspirin, levothyroxine, levothyroxineUnknown: omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, atorvastatin, atorvastatin, clopidogrel, clopidogrel, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Labetolol Disease Interaction

Major: bradyarrhythmia/AV block, cardiogenic shock/hypotension, CHF, diabetes, hemodialysis, hypersensitivity, ischemic heart disease, PVD, liver disease, asthma/COPDModerate: cerebrovascular insufficiency, glaucoma, hyperlipidemia, hyperthyroidism, hyperthyroidism PKs, myasthenia gravis, pheochromocytoma, psoriasis, tachycardia, Prinzmetal's variant angina

Volume of Distribution

In normotensive patients, the volume of distribution is 805L. In hypertensive patients, the volume of distribution is between 188-747L with an average of 392L.

Elimination Route

100mg and 200mg oral doses of labetalol have a T_max of 20 minutes to 2 hours. Bioavailability may be as low as 11% or as high as 86% and may increase in older patients or when taken with food.

Half Life

Labetolol has a half life of 1.7-6.1 hours.

Clearance

Labetolol has a plasma clearance of approximately 1500mL/min and a whole blood clearance of 1100mL/min.

Elimination Route

Radiolabelled doses of labetalol are 55-60% recovered in the urine and 12-27% recovered in the feces.

Pregnancy & Breastfeeding use

Pregnancy Category C. Teratogenic studies were performed with labetalol in rats and rabbits at oral doses up to approximately six and four times the maximum recommended human dose (MRHD), respectively. No reproducible evidence of fetal malformations was observed. Increased fetal resorptions were seen in both species at doses approximating the MRHD. A teratology study performed with labetalol in rabbits at IV doses up to 1.7 times the MRHD revealed no evidence of drug-related harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Labetolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Hypotension, bradycardia, hypoglycemia, and respiratory depression have been reported in infants of mothers who were treated with labetalol HCl for hypertension during pregnancy. Oral administration of labetalol to rats during late gestation through weaning at doses of two to four times the MRHD caused a decrease in neonatal survival.

Labor and Delivery: Labetolol HCl given to pregnant women with hypertension did not appear to affect the usual course of labor and delivery.

Nursing Mothers: Small amounts of labetalol (approximately 0.004% of the maternal dose) are excreted in human milk. Caution should be exercised when Labetolol Tablets are administered to a nursing woman.

Contraindication

Obstructive airway disease (e.g. bronchial asthma), 2nd and 3rd degree heart block, cardiogenic shock, conditions with severe or prolonged hypotension, uncompensated heart failure, severe bradycardia.

Special Warning

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Elderly Patients: As in the general population, some elderly patients (60 years of age and older) have experienced orthostatic hypotension, dizziness, or lightheadedness during treatment with labetalol. Because elderly patients are generally more likely than younger patients to experience orthostatic symptoms, they should be cautioned about the possibility of such side effects during treatment with labetalol.

Storage Condition

Store in cool dry place protected from light. Keep out of reach of children.

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